This proposal describes a multi-center trial for intervention therapy applied to relatives of patients with Type 1 diabetes who have a very high risk of developing overt clinical Type 1 diabetes within the next four years. Combinations of low dose subcutaneous and intravenous insulin will be given in a randomized, masked, four-arm trial of 'beta cell rest'. Three conditions were necessary to make this trial possible. The first was a method for identifying high risk subjects: we use a combination of parameters in relatives of patients with Type 1 diabetes to select a group with greater than 90 % chance of developing overt clinical diabetes within the next four years. The second was a beta cell specific treatment with low toxicity and evidence of efficacy in animal models and humans. Subcutaneous insulin treatment has prevented diabetes in both the NOD mouse and BB rat, and a pilot study in humans showed that it was safe and suggested efficacy. The last condition was the collaboration of centers with ongoing family screening programs, so that sufficient numbers of subjects can be identified and treated. Four major centers involved in family screening programs; Boston, Gainesville, Seattle and Denver agreed on the subject selection criteria and treatment protocols. The trial will have four arms. ARM A: 5 days of intravenous insulin in a clinical research center setting every 9 months, plus daily subcutaneous insulin at home, in a low dose. ARM B: 5 days of Intravenous insulin in a clinical research center setting every 9 months, no subcutaneous insulin at home. ARM C: 5 days of intravenous placebo in a clinical research center setting every 9 months, plus daily subcutaneous insulin at home, in a low dose. ARM D: 5 days of intravenous placebo in a clinical research center setting every 9 months, no subcutaneous insulin at home.